Dexmedetomidine Utilization During Air Medical Transport for Agitated Patients.

Fixed Wing Air Ambulance providers routinely transport patients agitated from traumatic brain injury sequelae across long distances in a unique environment. The current paradigm limits options available to air medical clinicians to those routinely found on ground based, short distance vehicles, plus whatever a sending facility might be willing to provide. We postulate that dexmedetomidine offers a safe, effective alternative to improve patient care and enhance the safe operation of aircraft.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia.

INTRODUCTION: Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises. OBJECTIVES: We tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function. METHODS: A genetic model of negative affect, the Wistar-Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5-3.5 mg·kg-1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1-1 mg·kg-1 systemic naloxone), quantification of plasma ß-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR). RESULTS: Monosodium iodoacetate-treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma ß-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization. CONCLUSIONS: Reduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain.

Combining two grading systems: the clinical validity and inter-observer variability of the 1973 and 2004 WHO bladder cancer classification systems assessed in a UK cohort with 15 years of prospective follow-up.

PURPOSE: Paucity of reliable long-term data on the prognostic implications of the 2004 WHO bladder cancer classification system necessitates utilisation of both this and the 1973 grading systems. This study evaluated, in noninvasive (pTa) bladder tumours, the prognostic value of the 2004 system independently and in combination with the 1973 system while establishing concordance between tertiary centre uropathologists. METHODS: We used a cohort of non-muscle invasive bladder cancer (NMIBC) patients diagnosed between 1991 and 93 where tumour features were gathered prospectively with detailed cystoscopic follow-up data recorded over 15 years. Initial grading was by one senior expert uropathologist (UP1) using the 1973 WHO classification alone. Subsequently, two other expert uropathologists (UP2 and UP3), blinded to the previous grading, re-evaluated the pathology slides and graded the tumours using both the 1973 and 2004 systems. Association between grade and recurrence/progression was analysed and the Cohen Kappa test assessed concordance between pathologists. RESULTS: Of 370 new NMIBC, 229 were staged noninvasive (pTa). Recurrence rates were 46.2% and 50.0% for LGPUC (low-grade papillary urothelial carcinoma) and HGPUC (high-grade papillary urothelial carcinoma), respectively, while progression was seen in 3.9% and 10.0% of LGPUC and HGPUC, respectively. Concordance between uropathologists UP2 and UP3 for the 2004 and 1973 systems was good (Kappa = 0.69) and fair (Kappa = 0.25), respectively. CONCLUSIONS: With good inter-observer concordance, the 2004 WHO classification system of noninvasive bladder tumours appears to accurately predict recurrence and progression risks. The combination of both grading systems to low-grade tumours allows further refinement of the natural history.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management.

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 µg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

The impact of anxiety on chronic musculoskeletal pain and the role of astrocyte activation.

Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

Water-based fractionation of a commercial humic acid. Solid-state and colloidal characterization of the solubility fractions.

BACKGROUND AND HYPOTHESIS: Humic acid (HA) is of considerable environmental significance, being a major component of soil, as well as being considered for application in other technological areas. However, its structure and colloidal properties continue to be the subject of debate, largely owing to its molecular complexity and association with other humic substances and mineral matter. As a class, HA is considered to comprise supramolecular assemblies of heterogeneous species, and herein we consider a simple route for the separation of some HA sub-fractions. EXPERIMENTS: A commercial HA sample from Sigma-Aldrich has been fractionated into two soluble (S1, S2) and two insoluble (I1, I2) fractions by successive dissolution in deionized water at near-neutral pH. These sub-fractions have been characterized by solution and solid-state approaches. FINDINGS: Using this simple approach, the HA has been shown to contain non-covalently bonded species with different polarity and water solubility. The soluble and insoluble fractions have very different chemical structures, as revealed particularly by their solid-state properties (13C NMR and IR spectroscopy, and TGA); in particular, S1 and S2 are characterized by higher carbonyl and aromatic contents, compared with I1 and I2. As shown by solution SAXS measurements and AFM, the soluble fractions behave as hydrophilic colloidal aggregates of at least 50nm diameter.

The dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia.

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03-0.3 mg/kg i.p.), and the atypical antipsychotic aripiprazole (1-3 mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioural alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs). Acute administration of cariprazine (0.1 and 0.3 mg/kg) and aripiprazole (3 mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3 mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioural tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in treatment of negative symptoms and functional impairment in schizophrenia patients.

Sonogashira cross-coupling and homocoupling on a silver surface: chlorobenzene and phenylacetylene on Ag(100).

Scanning tunneling microscopy, temperature-programmed reaction, near-edge X-ray absorption fine structure spectroscopy, and density functional theory calculations were used to study the adsorption and reactions of phenylacetylene and chlorobenzene on Ag(100). In the absence of solvent molecules and additives, these molecules underwent homocoupling and Sonogashira cross-coupling in an unambiguously heterogeneous mode. Of particular interest is the use of silver, previously unexplored, and chlorobenzene-normally regarded as relatively inert in such reactions. Both molecules adopt an essentially flat-lying conformation for which the observed and calculated adsorption energies are in reasonable agreement. Their magnitudes indicate that in both cases adsorption is predominantly due to dispersion forces for which interaction nevertheless leads to chemical activation and reaction. Both adsorbates exhibited pronounced island formation, thought to limit chemical activity under the conditions used and posited to occur at island boundaries, as was indeed observed in the case of phenylacetylene. The implications of these findings for the development of practical catalytic systems are considered.

5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT(6) receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT(6) receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT(6) receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT(6) agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT(6) antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT(6) receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.

Carbon-14 bioassay for decommissioning of Hanford reactors.

The production reactors at the U.S. Department of Energy Hanford Site used large graphite piles as the moderator. As part of long-term decommissioning plans, the potential need for ¹4C radiobioassay of workers was identified. Technical issues associated with ¹4C bioassay and worker monitoring were investigated, including anticipated graphite characterization, potential intake scenarios, and the bioassay capabilities that may be required to support the decommissioning of the graphite piles. A combination of urine and feces sampling would likely be required for the absorption type S ¹4C anticipated to be encountered. However, the concentrations in the graphite piles appear to be sufficiently low that dosimetrically significant intakes of ¹4C are not credible, thus rendering moot the need for such bioassay.

Blockade of dopamine D3 but not D2 receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment.

Dopamine D3 receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D3 vs. D2 receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D3 selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D3 antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D2 antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D3 receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D3 receptor antagonists to treat schizophrenia.

Disaggregating measurement uncertainty from population variability and Bayesian treatment of uncensored results.

In making low-level radioactivity measurements of populations, it is commonly observed that a substantial portion of net results is negative. Furthermore, the observed variance of the measurement results arises from a combination of measurement uncertainty and population variability. This paper presents a method for disaggregating measurement uncertainty from population variability to produce a probability density function (PDF) of possibly true results. To do this, simple, justifiable and reasonable assumptions are made about the relationship of the measurements to the measurands (the 'true values'). The measurements are assumed to be unbiased, that is, that their average value is the average of the measurands. Using traditional estimates of each measurement's uncertainty, a likelihood PDF for each individual's measurand is produced. Then using the same assumptions and all the data from the population of individuals, a prior PDF of measurands for the population is produced. The prior PDF is non-negative, and the average is equal to the average of the measurement results for the population. Using Bayes's theorem, posterior PDFs of each individual measurand are calculated. The uncertainty in these bayesian posterior PDFs appears to be all Berkson with no remaining classical component. The method is applied to baseline bioassay data from the Hanford site. The data include (90)Sr urinalysis measurements of 128 people, (137)Cs in vivo measurements of 5337 people and (239)Pu urinalysis measurements of 3270 people. The method produces excellent results for the (90)Sr and (137)Cs measurements, since there are non-zero concentrations of these global fallout radionuclides in people who have not been occupationally exposed. The method does not work for the (239)Pu measurements in non-occupationally exposed people because the population average is essentially zero relative to the sensitivity of the measurement technique. The method is shown to give results similar to classical statistical inference when the measurements have relatively small uncertainty.

S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization.

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.

Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex.

Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) receptor antagonist, S33084 (0.04-0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D(3) receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D(2) receptor antagonist, L741,626 (0.16-5.0 mg/kg), or with the dopamine D(3) agonist, PD128,907 (0.63-40 µg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of S33084 (2.5 µg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63-2.5 µg/side) improvement in NOR, while intra-striatal injection (2.5 µg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63-2.5 µg/side) impairment of NOR. These observations suggest that blockade of dopamine D(3) receptors enhances both SND and NOR, whereas D(3) receptor activation or antagonism of dopamine D(2) receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D(3) receptor antagonism.

Radiation doses to members of the U.S. population from ubiquitous radionuclides in the body: Part 1, autopsy and in vivo data.

This paper is Part 1 of a three-part series investigating steady-state effective dose rates to residents of the United States from intakes of ubiquitous radionuclides, including radionuclides occurring naturally, radionuclides whose concentrations are technologically enhanced, and anthropogenic radionuclides. This series of papers explicitly excludes intakes from inhaling (222)Rn, (220)Rn, and their short-lived decay products; it also excludes intakes of radionuclides in occupational and medical settings. In this work, it is assumed that instantaneous dose rates in target organs are proportional to steady-state radionuclide concentrations in source regions. The goal of Part 1 of this work was to review, summarize, and characterize all published and some unpublished data for U.S. residents on ubiquitous radionuclide concentrations in tissues and organs. Forty-five papers and reports were obtained and their data reviewed, and three data sets were obtained via private communication. The 45 radionuclides of interest are the (238)U series (14 nuclides), the actinium series (headed by (235)U; 11 nuclides), and the (232)Th series (11 nuclides); primordial radionuclides (87)Rb and (40)K; cosmogenic and fallout radionuclides (14)C and (3)H; and purely anthropogenic radionuclides (137)Cs-(137m)Ba, (129)I, and (90)Sr-(90)Y. Measurements judged to be relevant were available for only 15 of these radionuclides: (238)U, (235)U, (234)U, (232)Th, (230)Th, (228)Th, (228)Ra, (226)Ra, (210)Pb, (210)Po, (137)Cs, (87)Rb, (40)K, (14)C, and (3)H. Recent and relevant measurements were not available for (129)I and (90)Sr-(90)Y. A total of 11,741 radionuclide concentration measurements were found in one or more tissues or organs from 14 states. Data on age, gender, geographic locations, height, and weight of subjects were available only sporadically. Too often authors did not provide meaningful values of uncertainty of measurements, so that variability in data sets is confounded with measurement uncertainty. The following papers detail how these shortcomings are overcome to achieve the goals of the three-part series.

Radiation doses to members of the U.S. population from ubiquitous radionuclides in the body: Part 2, methods and dose calculations.

This paper is Part 2 of a three-part series investigating effective dose rates to residents of the United States from intakes of ubiquitous radionuclides, including radionuclides occurring naturally, radionuclides whose concentrations are technologically enhanced, and anthropogenic radionuclides. This series of papers explicitly excludes intakes from inhaling (222)Rn, (220)Rn, and their short-lived decay products; it also excludes intakes of radionuclides in occupational and medical settings. In this work, it is assumed that instantaneous dose rates in target organs are proportional to steady-state radionuclide concentrations in source regions. Part 1 reviewed, summarized, characterized, and grouped all published and some unpublished data for U.S. residents on ubiquitous radionuclide concentrations in tissues and organs. Assumptions about equilibrium with long-lived parents are made for the 28 other radionuclides in these series lacking data. This paper describes the methods developed to group the collected data into source regions described in the Radiation Dose Assessment Resource (RADAR) dosimetric methodology. Methods for converting the various units of data published over 50 y into a standard form are developed and described. Often, meaningful values of uncertainty of measurements were not published, so that variability in data sets is confounded with measurement uncertainty. A description of the methods developed to estimate variability is included in this paper. The data described in Part 1 are grouped by gender and age to match the RADAR dosimetric phantoms. Within these phantoms, concentration values are grouped into source tissue regions by radionuclide, and they are imputed for source regions lacking tissue data. Radionuclide concentrations are then imputed for the source regions of other phantoms with missing concentration values, and the uncertainties of the imputed values are increased. The concentrations of hollow organs' contents are calculated, and activities are apportioned to the bone source regions using assumptions about each radionuclide's bone-seeking behavior. The data sets are then ready to be used to estimate equivalent dose rates to target tissues from these source regions. The target tissues are then mapped to lists of tissues with International Commission on Radiation Protection (ICRP) tissue weighting factors, or they are mapped to surrogate tissue regions when there is no direct match. Effective dose rates, using ICRP tissue weighting factors recommended in 1977, 1990, and 2007, can be calculated from the tissue and organ equivalent dose rates. These effective dose rates are reported in Part 3 of this series.

Radiation doses to members of the U.S. population from ubiquitous radionuclides in the body: Part 3, results, variability, and uncertainty.

This paper is Part 3 of a three-part series investigating effective dose rates to residents of the United States from intakes of ubiquitous radionuclides, including radionuclides occurring naturally, radionuclides whose concentrations are technologically enhanced, and anthropogenic radionuclides. The radionuclides of interest are the (238)U series (14 nuclides), the actinium series (headed by (235)U; 11 nuclides), and the (232)Th series (11 nuclides); primordial radionuclides (87)Rb and (40)K; cosmogenic and fallout radionuclides (14)C and (3)H; and purely anthropogenic radionuclides (137)Cs-(137m)Ba, (129)I and (90)Sr-(90)Y. This series of papers explicitly excludes intakes from inhaling (222)Rn, (220)Rn, and their short-lived decay products; it also excludes intakes of radionuclides in occupational and medical settings. In this work, it is assumed that instantaneous dose rates in target organs are proportional to steady-state radionuclide concentrations in source regions. Part 1 reviewed, summarized, characterized, and grouped all published and some unpublished data for U.S. residents on ubiquitous radionuclide concentrations in tissues and organs. Part 2 described the methods used to organize the data collected in Part 1 and segregate it into the ages and genders defined by the study, including imputed missing values from the existing data, apportioned activity in bone, and imputed activity in hollow organ contents and the remainder of the body. This paper estimates equivalent dose rates to target tissues from source regions and maps target tissues to lists of tissues with International Commission on Radiation Protection (ICRP) tissue-weighting factors or to surrogate tissue regions when there is no direct match. Effective dose rates using ICRP tissue-weighting factors recommended in 1977, 1990, and 2007, are then calculated, and an upper bound of variability of the effective dose rate is estimated by calculating the average coefficients of variation (CV), assuming all variance is due to variability. Most of the data were for adult males, whose average effective dose rate is estimated to be 337 µSv y(-1) (CV = 0.65, geometric mean = 283 µSv y(-1), geometric standard deviation s(G) = 1.81) using 2007 ICRP tissue-weighting factors. This result is between the National Council on Radiation Protection and Measurements' 1987 estimate of 390 µSv y(-1) (using 1977 w(T)s) and its 2009 estimate of 285 µSv y(-1) (using 2007 w(T)s) and is higher than the United Nations Scientific Committee on the Effects of Atomic Radiation's 2000 estimate of 310 µSv y(-1) (using 1990 w(T)s). The methods and software developed for this project are sufficiently detailed and sufficiently general to be usable with autopsy data from any or all countries.

The dopamine D3 receptor antagonist, S33138, counters cognitive impairment in a range of rodent and primate procedures.

Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D(3) receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.01-0.63 mg/kg s.c.) blocked a delay-induced impairment of novel object recognition in rats, a model of visual learning and memory. Further, S33138 (0.16-2.5 mg/kg s.c.) similarly reduced a delay-induced deficit in social novelty discrimination in rats, a procedure principally based on olfactory cues. Adult rhesus monkeys were trained to perform cognitive procedures, then chronically exposed to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which produced cognitive impairment without motor disruption. In an attentional set-shifting task of cognitive flexibility involving an extra-dimensional shift, deficits were reversed by S33138 (0.04 and 0.16 mg/kg p.o.). S33138 also significantly improved accuracy (0.04 and 0.16 mg/kg p.o.) at short (but not long) delays in a variable delayed-response task of attention and working memory. Finally, in a separate set of experiments performed in monkeys displaying age-related deficits, S33138 significantly (0.16 and 0.63 mg/kg p.o.) improved task accuracies for long delay intervals in a delayed matching-to-sample task of working memory. In conclusion, S33138 improved performance in several rat and primate procedures of cognitive impairment. These data underpin interest in D(3) receptor blockade as a strategy for improving cognitive performance in CNS disorders like schizophrenia and Parkinson's disease.

Sonogashira coupling on an extended gold surface in vacuo: reaction of phenylacetylene with iodobenzene on Au(111).

Temperature-programmed reaction measurements supported by scanning tunneling microscopy have shown that phenylacetylene and iodobenzene react on smooth Au(111) under vacuum conditions to yield biphenyl and diphenyldiacetylene, the result of homocoupling of the reactant molecules. They also produce diphenylacetylene, the result of Sonogashira cross-coupling, prototypical of a class of reactions that are of paramount importance in synthetic organic chemistry and whose mechanism remains controversial. Roughened Au(111) is completely inert toward all three reactions, indicating that the availability of crystallographically well-defined adsorption sites is crucially important. High-resolution X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy show that the reactants are initially present as intact, essentially flat-lying molecules and that the temperature threshold for Sonogashira coupling coincides with that for C-I bond scission in the iodobenzene reactant. The fractional-order kinetics and low temperature associated with desorption of the Sonogashira product suggest that the reaction occurs at the boundaries of islands of adsorbed reactants and that its appearance in the gas phase is rate-limited by the surface reaction. These findings demonstrate unambiguously and for the first time that this heterogeneous cross-coupling chemistry is an intrinsic property of extended, metallic pure gold surfaces: no other species, including solvent molecules, basic or charged (ionic) species are necessary to mediate the process.